Abstract
ABSTRACT
Neutrophil extracellular traps (NETs) perpetuate chronic inflammation in ulcerative colitis (UC), yet current neutrophil‐targeting therapies focus on acute intervention rather than sustained daily control. Here, we propose an oral microsupplement for long‐term UC management that concurrently scavenges reactive oxygen species (ROS) and suppresses NET formation. The microsupplement integrates a catalase‐mimetic CoAl‐layered double hydroxide (LDH) nanozyme intercalated with the autophagy inhibitor chloroquine (CQ), together with dopamine (DOPA). The LDH nanozyme catalytically converts pathological ROS into oxygen, driving in situ polymerization of DOPA into polydopamine (PDA), a mucoadhesive polymer that prolongs colonic retention of CQ@LDH and promotes mucosal healing. RNA sequencing reveals that internalized CQ@LDH inhibits autophagic flux in neutrophils, thereby upregulating catalase expression and peroxisomal function to prevent NET formation. Consequently, NET‐driven M1 macrophage polarization is reduced from 29.5% to 17.9%, and Th17 differentiation is markedly suppressed, accompanied by a decrease in colonic Th17/Treg ratio from 8.68 to 1.31. In a murine UC model, this microsupplement restores colonic mucosal integrity, rebalances the gut microbiota, and outperforms the clinical drug 5‐aminosalicylic acid in both immune regulation and epithelial restitution. This neutrophil‐regulating, colon‐adhesive platform offers a promising strategy for routine daily UC management.